This program project grant consists of four highly interrelated projects led by rheumatology faculty at Columbia involved in basic and clinical research relevant to autoimmune disease. The four projects represent logical extensions of recent advances at Columbia that have revealed novel cellular and molecular mechanisms important in the normal control of immune responses by either cytokines and/or chemokines (IL-4, IFN-gamma) cell surface molecules (CD40-Lm FAS), or regulatory T-T cell interactions. Our goal is to establish and continue to foster collaborative interactions in these areas and focus the research in this PPG directly on mechanisms of autoimmunity. In project #1, Dr. Rothman will further define the role of the beta chain of the IFNgammareceptor (termed AF-1) in the differentiation and function of T cell subsets. He will utilize two AF-1transgenics to explore the biology of AF-1 in the differentiation of TH1 and TC1 subsets in normal animals and in animals with experimental allergic encephalomyelitis (EAE). In project #2, Dr. Fiang will further explore in vivo and in vitro the role of CD8+ regulatory T cells induced by T cell vaccination in controlling the outgrowth of CD4+, Vbeta8+ T cells in normal mice and in mice with EAE. Collaborative interactions with Dr. Rothman will study the influence of AF-1 genes in these CD8/CD4 interactions. Moreover, in Project #3 Drs. Chess and Braunstein will extend these studies of Vbeta specific CD8+ T cells to the molecular analysis of effector mechanisms. These studies will involve the direct analysis of murine autoimmune models with known defects in apoptotic functions (FAS (1pr) and FAS-L, (gld) deficient strains) and CD8 cells that regulate EAE. In Project, #4, Dr. Winchester will focus on characterizing the immunomodulating potential of mesenchymal cell products by analyzing cultured fibroblastoid cells from rheumatoid arthritis synovitis as a prototype of mesenchymal cell genes identified as important in synovitis will be studied in EAE and the other murine models of autoimmune disease in Projects #1, #2 and #3. In summary, the proposed PPG should enable and promote synergistic collaborative interactions aimed at defining regulatory mechanisms mediated by lymphocytes and/or cytokines involved in the pathogenesis of autoimmune disease.